Basil P. Hubbard

The goal of the Hubbard lab is to develop next-generation therapeutics for the treatment of a wide-variety of age-related (e.g. cancer), genetic, and infectious diseases. Our work is interdisciplinary and incorporates experimental techniques that fuse elements of chemistry, biochemistry, biophysics, pharmacology, and molecular and synthetic biology. In addition to our applied research aimed at generating new therapeutics, we also engage in basic biology and pharmacology projects that explore poorly understood processes that could lay the foundation for new areas of research and technology development. Research in our lab is grouped into three themes:

1) Gene Editing Tools & Macromolecular Therapeutics

Gene editing technologies such as CRISPR are transforming genetic engineering studies in the lab, and are poised to revolutionize medicine in the near future. Our group is working towards removing some of the current limitations of these technologies (e.g. Cas9, Cas12, Cas13) to make them safe and effective for clinical use. In particular, we are using protein and RNA engineering to improve the specificity of these tools, such that only the correct target gene is ever cut, and exploring new methods for their delivery into cells and tissues. We are also harnessing the capabilities of these proteins and others to generate ‘smart’ protein-based therapeutics, capable of sensing and responding to cellular events, to treat a number of diseases.

2) Synthetic & Xenobiology

Synthetic biology is a field focused on engineering or re-designing cells, genes, and pathways. Our group is interested in engineering various types of cells to combat disease (e.g. cell-based therapies). Xenobiology is a sub-branch of synthetic biology that seeks to modify the fundamental building blocks of life, including nucleic acids and polypeptides. For example, chemically-modified nucleic acids, also called xenonucleic acids (XNAs), are commonly used in nucleic acid-based therapeutics developed by the pharmaceutical industry because they demonstrate superior serum stability compared to natural DNA and RNA. Our group is working on using these synthetic nucleic acids to improve the specificity of gene editing agents. We are also exploring if XNAs can be stably incorporated into living cells and organisms for a variety of applications.

3) Molecular Pharmacology

Molecular pharmacology studies the biochemical and biophysical interactions between drugs and their targets and cellular pathways. Our group is interested in identifying new target proteins for age-related diseases such as cancer, and in developing strategies to regulate these targets using conventional small-molecule drugs or macromolecular therapeutics. We perform genetic screens to identify new targets, and early stage drug discovery work such as small-molecule screens to identify lead compounds for further development. Our most recent work in this area has focused on the discovery of small-molecule inhibitors of Nsp15, a protein used by SARS-CoV-2 for immune evasion.

Select Publications

A conserved acetylation switch enables pharmacological control of tubby-like protein stability.
Kerek EM, Yoon KH, Luo SY, Chen J, Valencia R, Julien O, Waskiewicz AJ, Hubbard BP.
Journal of Biological Chemistry. 2021 Jan-Jun;296:100073. 

CRISPR Lights up In Situ Protein Evolution.
Kerek EM, Cromwell CR, Hubbard BP.
Cell Chemical Biology. 2020 May 21;27(5):475-478. 

Incorporation of bridged nucleic acids into CRISPR RNAs improves Cas9 endonuclease specificity.
Cromwell CR, Sung K, Park J, Krysler AR, Jovel J, Kim SK, Hubbard BP. 
Nature Communications. 2018 Apr 13;9(1):1448.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging.
Li J, Bonkowski MS, Moniot S, Zhang D, Hubbard BP, Ling AJ, Rajman LA, Qin B, Lou Z, Gorbunova V, Aravind L, Steegborn C, Sinclair DA.
Science. 2017 Mar 24;355(6331):1312-1317. 

Continuous directed evolution of DNA-binding proteins to improve TALEN specificity.
Hubbard BP, Badran AH, Zuris JA, Guilinger JP, Davis KM, Chen L, Tsai SQ, Sander JD, Joung JK, Liu DR.
Nature Methods. 2015 Oct;12(10):939-42.